Jerry Tan MD FRCPC University of Western Ontario Windsor campus, Ontario, Canada. Pathogenesis & management of acne scarring

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1 Jerry Tan MD FRCPC University of Western Ontario Windsor campus, Ontario, Canada Pathogenesis & management of acne scarring

2 Disclosures Relationships with commercial interests: Abbott Laboratories A(Grants/Research Funding); Allergan, Inc I(Grants/Research Funding); Avène SP(H); Bayer Pharmaceuticals C(Grants/Research Funding); Boots C(H); Cipher Pharmaceuticals C(H), I(Grants/Research Funding); Dermira I(Grants/Research Funding); Eli Lilly and Company I(Grants/Research Funding); Galderma Laboratories, L.P. A(H), I(Grants/Research Funding); Galderma Research & Development, LLC C(H); Hoffman-La Roche Ltd. C(H); Janssen Pharmaceuticals, Inc I(Grants/Research Funding); Leo Pharma Inc. I(Grants/Research Funding); Lilly ICOS LLC I(Grants/Research Funding); Pfizer Inc. I(Grants/Research Funding); Procter & Gamble Company A(H); Stiefel a GSK company A(H), I(Grants/Research Funding); Valeant Pharmaceuticals International A(H); Xenon Pharmaceuticals C(Grants/Research Funding)

3 Background Prevalence Impact Development of atrophic acne scars Clinical Basic science Management Prevention Reduction Correction Agenda

4 Background Prevalence Impact RISK FACTORS? Development of atrophic acne scars Clinical Basic science ARE THEY PERMANENT? DOES INFLAMMATION DIFFER? Management Prevention Reduction Correction EVIDENCE FOR REDUCTION? CORRECTION? Agenda/Controversies

5 Percent of subjects Prevalence of Scarring with Acne Severity 100% Percentage of Patients with Acne Scars 80% 77% 60% 51% 40% 20% 0% 28% Almost clear or mild acne Moderate acne Severe acne 43% of all patients (n=1,972) had acne scars Adapted from Tan J et al. J Drugs Dermatol 2017; 16(2):97-102

6 Number of patients Acne Scars can adversely impact Quality of Life (DLQI) 25 No effect/ Mild effect (0-5) Moderate effect/ Very large effect (6-20) Mild Moderate Severe DLQI, Dermatology Life Quality Index; Adapted from Hazarika N and Archana M Indian J Dermatol. 2016: 61(2):

scars Clear skin 20 20 14 12 6 11 41 8 NO ACNE SCARS ACNE SCARS Adapted from Dréno

7 How People with Facial Acne Scars are Perceived Multi-national online survey (4,618 responders) First Thing Noticed About a Person s Face Acne scars Clear skin NO ACNE SCARS ACNE SCARS Adapted from Dréno B, et al. Dermatol Ther (Heidelb) 2016;6(2): Eye Hair Mouth Nose Skin All p<0.05

8 How People with Facial Acne Scars are Perceived Traits of Individuals Attractive Confident Healthy Skills of Individual Public speaking Sports Impact on Individual s Life Stressed Make people uncomfortable Unhappy with their life All p<0.05 Acne Scars (%) (n=6956 pictures) Clear skin (%) (n=6898 pictures) Adapted from Dréno B, et al. Dermatol Ther (Heidelb) 2016;6(2):

9 Risk Factors for Acne Scars RISK FACTOR CATEGORY THRESHOLDS ODDS RATIOS [CI] Severity of acne Severe-very severe vs. Almost clear-moderate 3.68 [ ] Family history of acne scarring Yes vs. No 2.14 [ ] Duration of acne 1 year or more vs. 1 year or less 1.63 [ ] Squeezing and picking behaviours Frequently all the time vs. Never sometimes 1.70 [ ] Adapted from Tan J et al. J Eur Acad Dermatol Venereol Sep;31(9):

10 Atrophic acne scar formation from primary acne lesions 6 month observational study of moderate inflammatory acne with digitized facial mapping Tan et al. Prospective Study of Pathogenesis of Atrophic Acne Scars and Role of Macular Erythema. J Drugs Dermatol Jun 1;16(6):

11 36% of scars disappeared at 6 months Ongoing acne scar formation & repair Tan et al. Prospective Study of Pathogenesis of Atrophic Acne Scars and Role of Macular Erythema. J Drugs Dermatol Jun 1;16(6):

12 Response Immune Responses in Patients Prone to Scarring TLR 4 Innate Inflammatory Cytokines (IL-2) innate adaptive Not Prone to Scarring Prone to Scarring Vascular adhesion molecules Th17 CD4 + T Cells Adaptive Plasma Cells Adapted from Saint-Jean et al. Eur J Dermatol 2016; 26(1): 68-74; Holland DB et al. Br J Dermatol 2004; 150:72-81; Carlavan I et al. Br J Dermatol (4): ; Time

13 Atrophic Acne Scar Management I. Prevention

14 No acne Premise No acne scars

15 Atrophic Acne Scar Management II. Mitigation

16 Delay to effective acne treatment correlates with scar prevalence Tan J, et al. J Cutan Med Surg. 2010;14:

17 Isotretinoin for Prevention of Acne Scarring Design Prospective clinical study Moderate to severe acne (n=107) Study Treatment Once daily, isotretinoin 1 mg/kg/day for 4 months (cumulative dose of 120 mg/kg) Layton AM et al. Dermatol 1997; 195(Suppl 1):15-21

18 Mean Scarring Score Earlier treatment with isotretinoin reduced scar severity *p< * <3 years acne duration >3 years acne duration Adapted from Layton AM et al. Dermatol 1997; 195(Suppl 1):15-21

19 P. acnes induces MMP-9 and TIMP in human monocytes Matrix Repair Capability of Tretinoin in vitro Tretinoin modulates MMP- 9/TIMP expression, shifting from a matrix-degradative phenotype to a matrixpreserving phenotype Treatment of monocytes with tretinoin (all-trans retinoic acid) inhibits MMP-9 and augments TIMP-1 expression MMP, matrix metalloproteinases; TIMP; tissue inhibitor of metalloproteinase; Jalian HR et al. J Invest Dermatol, 2008; 128:

20 Adapalene 0.3% Gel Improves Skin Texture and Appearance of Atrophic Acne Scars Design 24-week, open-label study (n=20) Patients with past history of acne (no active lesions at time of enrollment) Moderate to severe facial atrophic acne scars Grade 3 or 4* and 5 atrophic scars Study Treatments Adapalene 0.3% once daily for first 4 weeks, then twice daily for 20 weeks Daily skin care: Skin cleanser, moisturizing lotion and SPF50 sunscreen Loss MJ et al. Dermatol Ther (Heidelb) Jun;8(2):

21 % OF SUBJECTS 100% 77.8% 50% Adapalene 0.3% Gel: Improvement in scar severity 22.2% 0% 0.0% No change Slight improvement Moderate to complete improvement IGA, Investigator s Global Assessment; Adapted from Loss MJ et al. Dermatol Ther (Heidelb) Jun;8(2):

22 Increased Procollagen-1 by 15% Collagen-3 by 58% Enhanced Collagen Synthesis with Adapalene 0.3% Loss MJ et al. Dermatol Ther (Heidelb) Jun;8(2):

Design 6-month split-face, investigator-blinded, vehiclecontrolled study Randomized controlled trial Moderate facial acne 10 atrophic acne scars at

23 Design 6-month split-face, investigator-blinded, vehiclecontrolled study Randomized controlled trial Moderate facial acne 10 atrophic acne scars at baseline (n=31) Adapalene 0.1%/BPO 2.5% Split-Face Study A0.1/BPO2.5, adapalene 0.1%/benzoyl peroxide 2.5%; J Eur Acad Dermatol Venereol Apr;31(4):

24 Mean scar count % almost clear (SGA) A0.1%/BPO 2.5% Reduces Risk of Atrophic Scars and Improves Scar Severity p= Baseline 6 Months Vehicle A/BPO Baseline 45.2 p= Months Vehicle A/BPO A0.1/BPO2.5, adapalene 0.1%/benzoyl peroxide 2.5%; J Eur Acad Dermatol Venereol Apr;31(4):

25 Adapalene 0.3%/BPO 2.5% Gel in acne and acne scarring (OSCAR Study) Design 24-week split-face, investigatorblinded, vehicle-controlled study Moderate to severe facial acne (n=67) Once daily vehicle gel Once daily A0.3/BPO2.5 gel Dréno B et al. Am J Clin Dermatol Apr;19(2):

26 Change from baseline (%) Acne Global Success (%IGA clear/almost clear) 100 Vehicle A0.3/BPO * 1.5 *p< A0.3/BPO2.5, adapalene 0.3%/ benzoyl peroxide 2.5%; IGA, Investigator Global Assessment * * * * Weeks * * Dréno B et al. Am J Clin Dermatol Apr;19(2):

27 Acne Scar Results 50% Atrophic Scar Count Change from Baseline 40% 30% ** 32.9% 30 20% % 0% A0.3/BPO2.5 (N=67) 16.4% Vehicle (N=67) * * -4.5 * * * -8.7 * SGA clear/almost clear (week 24) -30 * Week *p<0.001; **p< A0.3/BPO2.5, adapalene 0.3%/ benzoyl peroxide 2.5%; SGA, Scar Global Assessment; Adapted from Dréno B et al. Am J Clin Dermatol Epub ahead of print

28 Atrophic Acne Scar Management III. Correction/Repair

29 Patients present with multiple types of acne scars

30 Depth Types of Atrophic Acne Scars Icepick Rolling Boxcar Super Boxcar >4 mm Skin surface Superficial musculoaponeurotic system Tethering by scar tissue under all scar types Jacob et al. J Am Acad Dermatol Jul;45(1):109-17

31 Modalities for Acne scar treatment Scar Type Ice pick Boxcar Rolling Treatment Modalities Chemical peel (CROSS technique), punch techniques, RF Dermabrasion (shallow), dermal fillers (shallow), lasers (ablative, nonablative, fractional; shallow), punch techniques (deeps), RF (shallow, deep), skin needling (shallow), subcision (shallow) Dermabrasion, dermal fillers, lasers (ablative, nonablative, fractional), RF, skin needling, subcision RF, radiofrequency; CROSS, chemical reconstruction of skin scars; PDL, pulsed dye laser; Lanoue J and Goldenberg G Cutis. 2015;95:

32 Effectiveness of Correction Procedures for Acne Scarring Modality Ice Pick Scars Boxcar Scars Rolling Scars Chemical Peels TCA CROSS technique Dermabrasion/microdermabrasion Laser Ablative and nonablative laser Fractional laser photothermolysis Punch Techniques Punch excision Punch elevation Punch replacement grafting Tissue augmenting agents Needling Subcision = effective, + = less effect, - = not effective TCA/CROSS, trichloroacetic acid/chemical reconstruction of skin scars; Adapted from Gozali MV and Zhou B. J Clin Aesthet Dermatol. 2015;8(5):

33 Atrophic Acne Scar Algorithm (Level I evidence in blue bold) Atrophic Acne Scars Topical retinoids Peels (GA, TCA, Phenol) Ice Pick TCA CROSS Punch excision KEY: TCA CROSS: trichloroacetic acid chemical reconstruction of skin scars; PRP, platelet-rich plasma; RF: radiofrequency Boxcar TCA CROSS Lasers: ablative & nonablative Microneedling ± PRP RF: microneedle or fractional bipolar Dermabrasion Punch elevation Rolling Subcision Lasers: ablative & non-ablative Microneedling ± PRP RF: microneedle or fractional bipolar Fillers Adapted from Connolly D et al. J Clin Aesthet Dermatol. 2017; 10(9):12-23 and Bhargava et al. Am J Clin Derm 2018; 19:

34 Background Prevalence Impact RISK FACTORS? Development of atrophic acne scars Clinical Basic science ARE THEY PERMANENT? DOES INFLAMMATION DIFFER? Management Prevention Reduction Correction EVIDENCE FOR REDUCTION? CORRECTION? SUMMARY /Controversies

35 Modifiable risk factors in scarring duration, severity, manipulation Scarring results from intensity and duration of inflammation; inadequate matrix repair Atrophic acne scars can repair spontaneously Topical retinoids can reduce scar formation Acne scarring can be reduced and corrected Key Messages: Atrophic acne scarring

ACNE BOOT CAMP TOPICAL THERAPY BASICS

ACNE BOOT CAMP TOPICAL THERAPY BASICS Lawrence J Green, MD Associate Clinical Professor of Dermatology George Washington University School of Medicine Washington DC Relevant Disclosures Investigator -Allergan,